1. Field of the Invention
The present invention relates to a process for the resolution of amines by reaction with an ester as an acyl donor in the presence of a hydrolase and subsequent separation of the enantiomerically enriched amide from the unreacted, enantiomerically enriched amine.
2. Description of the Related Art
The resolution of amines by enzyme-catalyzed reaction with esters is known in various embodiments in the literature. In an early study, the resolution of amines using trifluoroethyl butyrate as the acyl donor and subtilisin as the enzyme component is already described in 1989 (H. Kitaguchi, P. A. Fitzpatrick, J. E. Huber, A. M. Klibanov, J. Am. Chem. Soc. 1989, 111, 3094). However, selectivities varying in a wide range were obtained. The reaction times were also in a range which is unsatisfactory for industrial applications.
A large number of studies are based on the use of alkyl acetates, for example using ethyl acetate and butyl acetate. In a first general synthesis, for this purpose high enantiomeric excesses of 90-98% ee for the amide formed were obtained using ethyl acetate as the acyl donor and a lipase from Candida antarctica (M. T. Reetz, C. Dreisbach, Chimia 1994, 48, 570). However, the conversions were in a wide range from 20-44%, although large amounts of enzyme were used as a catalyst. The reaction times were also in a wide range from 7 to 60 hours.
A detailed investigation of this method confirmed the long reaction times, which when using ethyl acetate as the acyl donor and a lipase from C. antarctica were between 5 and 21 days (B. A. Davis, D. A. Durden, Synth. Commun. 2001, 31, 569). Acyl donors having prolonged chain lengths were likewise employed, but when using ethyl decanoate as the acyl donor and a lipase from C. antarctica only led to a low conversion (A. Goswami, Z. Guo, W. L. Parker, R. N. Patel, Tetrahedron: Asymmetry 2005, 16, 1715).
The use of ethyl methoxyacetate as an acyl donor in the enzymatic resolution of amines using a lipase from Burkholderia plantarii led to a high reaction rate, the use of MTBE as the preferred solvent being emphasized (F. Balkenhohl, K. Ditrich, B. Hauer, W. Ladner, J. Prakt. Chem. 1997, 339, 381; Review: M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keβeler, R. Stürmer, T. Zelinski, Angew. Chem. 2004, 116, 806). However, large amounts of enzyme of >10 000 000 units per mole of substrate are also employed. The resolution using ethyl methoxyacetate likewise proceeds successfully when using a lipase from Candida antarctica as a biocatalyst (U. Steltzer, C. Dreisbach, DE Pat. 19637336, 1996).
Further enzymatic resolution methods are based on the use of dialkyl, diallyl and divinyl carbonates (C.-H. Wong, B. Orsat, W. J. Moree, S. Takayama, U.S. Pat. No. 5,981,267, 1999; B. Orsat, P. B. Alper, W. Moree, C.-P. Mak, C.-H. Wong, J. Am. Chem. Soc. 1996, 118, 712). Using phenylallyl carbonate, an “unsymmetrically substituted” carbonate was additionally also found to be a suitable acyl donor for the lipase-catalyzed resolution of amines (G. F. Breen, Tetrahedron: Asymmetry 2004, 15, 1427). However, the unsatisfactory enantioselectivities often obtained are disadvantageous.
Moreover, ethyl acrylates were also employed as esters in the enzymatic resolution of aliphatic amines, high enantiomeric excesses of up to 95% ee being obtained for the remaining amine (S. Puertas, R. Brieva, F. Rebolledo, V. Gotor, Tetrahedron 1993, 49, 4007). However, the reaction times were a long 7 to 11 days, which is not appealing for industrial use.
A further acyl donor employed is cyanomethyl pent-4-enoate, cost-effective access to this acyl donor being problematical (S. Takayama, W. J. Moree, C.-H. Wong, Tetrahedron Lett. 1996, 37, 6287).
In EP 865500, the enzymatic resolution of amides is mentioned, compounds of the general formula 1 being reacted in the presence of the lipase from Candida antarctica.

X here can be both oxygen and sulphur. Only examples for X=O are shown.